1. Field of the Invention
The present invention relates to boron-containing compounds useful in boron neutron capture therapy of tumors and to methods for using such compounds. The compounds of the present invention provide a means for directly quantifying boron concentrations in tissue, thereby permitting rapid enhanced targeting and planning of neutron-capture irradiation of tumors.
2. Background of the Related Art
Cancer continues to be one of the foremost health problems. Conventional treatments such as surgery, photon radiation therapy, and chemotherapy have been successful in certain cases and unsuccessful in others. An unfamiliar form of radiation therapy for cancer, known as Boron Neutron-Capture Therapy (BNCT), is being investigated to treat certain tumors for which the conventional methods have been ineffective. For example, BNCT has been used clinically in Japan to treat glioblastoma multiforme, a highly malignant, invasive form of brain cancer.
BNCT is an anti-cancer bimodal radiation therapy that utilizes the ability of the stable (non-radioactive) nucleus boron-10 (.sup.10 B) to absorb thermal neutrons. In BNCT of malignant brain tumors, the patient is first given an infusion of a boron-containing compound that is highly enriched in the .sup.10 B isotope. Ideally, the boronated compound concentrates preferentially in the brain tumor. For some boron compounds under investigation in BNCT research, the action of the blood-brain-barrier generally minimizes their entry into the surrounding brain tissues. The tumor area is then irradiated with a beam of thermal neutrons (primary irradiation), some of which are captured by the boron-10 concentrated in the tumor. The relative probability that the slow-moving thermal neutrons will be absorbed by the boron-10 nuclide is high compared to the probability of absorption by most all other nuclides in the tissue combined, i.e., the nuclides normally present in mammalian tissues. Boron-10 undergoes the following nuclear reaction when captured by a thermal neutron: EQU .sup.10 B+n.fwdarw.*.sup.11 B, EQU *.sup.11 B.fwdarw..sup.7 Li+.sup.4 He+.gamma.(478 keV)
In this nuclear reaction, a .sup.10 B nucleus absorbs a neutron, forming the metastable nuclide *.sup.11 B, which spontaneously disintegrates into a .sup.4 He particle and a .sup.7 Li particle, bearing a total kinetic energy of 2.34 MeV. These two particles have 9 .mu.m and 5 .mu.m ranges in tissue, respectively. Accordingly, the particles are capable of destroying cells such as cancer cells, and/or cells of the blood vessels in the tumor that allow the cancer to grow, the nuclei of which are in their trajectories. In effect, the tumor alone is preferentially irradiated with these high linear energy transfer (LET) alpha and .sup.7 Li particles whose range in tissue is about 10 .mu.m, a distance comparable to the diameter of an average cell. Therefore, the efficacy of BNCT resides in the production of highly localized, ionizing radiation in the target tissue. In this manner, the tumor receives a relatively large radiation dose, compared to that received by the surrounding healthy tissue. Optimally, the preferential accumulation of boron-10 in the tumor permits the radiation dose to the tumor to exceed the dose to the blood vessels of the surrounding normal brain and to greatly exceed the dose to the extravascular normal brain tissue.
Several criteria must be met in order for radiation enhancement provided by BNCT to be successful. First, the .sup.10 B must be present in significant quantities at the tumor site (at least about 10 mg, and preferably more than about 30 mg .sup.10 B/g tissue). Second, there should be high selectivity of the drug for the tumor over normal tissue, with tumor-to-normal tissue ratios greater than two. Generally, this second criterion is satisfied if the boronated drug does not penetrate the blood brain barrier. Third, the tumor-to-blood ratio should be not less than one. Fourth, the boronated drug should not be significantly toxic to the patients being treated. However, considering the seriousness of malignant brain tumors, moderately toxic chemotherapeutic agents and other therapeutic agents are widely used.
BNCT differs from other cancer therapy modalities. For example, BNCT differs from conventional radiotherapy modalities because it uses an external beam to produce a high radiation dose only where a chemical compound has accumulated prior to irradiation. BNCT also differs from chemotherapy because the compound that accumulates in the tumor expresses its tumoricidal action only within the field of the neutron radiation beam. The efficacy of BNCT therefore depends not only upon the relative concentrations of boron in the blood, in the tumor and in other vital tissues within the treatment volume, but also depends upon the quality of the neutron beam.
The concentrations of .sup.10 B within the tissues of patients have been estimated indirectly by pharmacokinetic extrapolation from the concentration of .sup.10 B in blood and tissue samples from patients and from experimental animals. Such extrapolations are approximate. It would therefore be desirable to have a method for more directly, more rapidly, and more accurately determining the concentration and distribution of .sup.10 B in a patient being prepared for BNCT. The implementation of rapid BNCT treatment planning, enabled by relatively common and cost effective imaging techniques such as computerized tomography (CT) and nuclear medicine scintigraphy, would greatly facilitate the clinical acceptance and efficacy of BNCT.
The simultaneous labeling of antibodies with .sup.10 B and with other nuclides, including iodine, for purposes of imaging tumors and targeting thermal neutron radiation exposures are described in U.S. Pat. Nos. 4,348,376 to Goldenberg, 4,665,897 to Lemelson, and 4,824,659 to Hawthorne. Each of these patents, however, requires that the .sup.10 B compound be linked to a radio-labeled antibody. None of these patents discloses boron compounds that are targeted nonspecifically, nor do they disclose nonradioactive iodination of boron-containing compounds for imaging. In addition, the iodine is described in these patents as being directly substituted for hydrogen atoms on the antibody molecule, but not into the borane moiety.
Specifically, U.S. Pat. No. 4,348,376 to Goldenberg describes methods for radiolabeling antibodies to carcinoembryonic antigen (CEA), a cell surface marker commonly associated with certain types of tumors. The anti-CEA antibodies are described as being coupled to a .sup.10 B-containing moiety including, for example, the diazonium ion derived from 1-(4-aminophenyl)-1,2-dicarbacloso-dodecaborane. Goldenberg further describes methods for radiolabeling the boron-rich antibody complex using any of a group of radioisotopes that emit detectable particle or photon radiation, for example, iodine-131 (.sup.131 I), iodine-123 (.sup.123 I), or iodine-125 (.sup.125 I).
U.S. Pat. No. 4,665,897 to Lemelson discloses a method of radiolabeling antibodies, desirably antibodies specific for tumors. Lemelson describes a variety of boron-containing moieties that may be coupled to the antibodies. Lemelson also describes the additional coupling of radionuclides, including isotopes of iodine, to the antibody moiety of the boron-coupled antibodies. The isotopes used for imaging of the target tissues are described by Lemelson as either stable or radioactive, allowing for targeting by imaging of either stimulated or spontaneous emission of radiation. Lemelson does not describe boranes as added moieties or the iodination of boranes, nor does Lemelson describe a method for adding sufficient stable iodine to antibodies in amounts that would allow chemical noninvasive imaging while also allowing the antibodies to retain their antigenic specificity for a tumor.
U.S. Pat. No. 4,824,659 to Hawthorne describes the modification of antibodies by coupling them to a synthetic poly(amide/urea/thiourea) moiety containing any of various boranes, resulting in antibody conjugates carrying 50-2000 boron atoms with about 96% .sup.10 content. The Hawthorne patent describes a variety of other antibody conjugates, including antineoplastic agents, paramagnetic spin labels, chromogens, etc., in addition to .sup.10 B borane compounds. Hawthorne also describes the coupling of radionuclides, including isotopes of iodine, to the antibody moiety of the borane-antibody complex, for in vivo diagnostic use.
The use of radioisotope-labeled therapeutic substances for purposes of PET imaging of blood concentration and feedback control of the rate of administration of the labeled substances is described in U.S. Pat. No. 4,409,966 to Lambrecht et al. The Lambrecht et al. patent, however, does not disclose compounds containing boron for BNCT. Lambrecht et al. also describe the application of their method to the injection of other radiopharmaceuticals. Unlike the present invention, Lambrecht et al. employ a pharmaceutical labeled with a positron-emitting isotope for detection by Positron Emission Tomograph (PET). Lambrecht et al. do not describe the use of .sup.10 B carriers as an aspect of their method. Nor do they describe the use of the technique for imaging drug concentrations around tumors or for the targeting of radiation therapy.
Thiouracil derivatives of decaboranes used for BNCT are described in U.S. Pat. Nos. 5,116,980 and 5,144,026 to Gabel. These patents disclose a variety of compounds and their intermediates that may be used for BNCT, but do not describe labeling of the compounds for imaging purposes. They disclose halogenated boranes such as omega-carboranyl acyl halides. Gabel does not describe the use of these compounds as therapeutic agents. Rather, the compounds are described as intermediates in the reactions required to produce the therapeutic thiouracil derivatives. Further, Gabel does not disclose imaging of blood concentrations of .sup.10 B carriers. The Gabel patents do not describe the use of nuclide-labeled .sup.10 B carriers for simultaneous imaging and therapeutic use in BNCT.
A review of the history of BNCT as applied to brain tumors is provided in a publication by one of the co-inventors, Slatkin, "A History of Boron Neutron Capture Therapy of Brain Tumours", Brain 114 1609-1629 (1991). This article describes uses of .sup.10 B carriers before 1991, such as sulfidohydroboranes, including Na.sub.2 B.sub.12 H.sub.11 SH (a monomer hereinafter abbreviated BSH) and Na.sub.4 B.sub.24 H.sub.22 S.sub.2 (a dimer hereinafter abbreviated BSSB). Slatkin mentions the need for techniques capable of generating data on the distribution of BNCT agents in patients, but does not describe any means for noninvasive imaging of .sup.10 B-carriers. Slatkin also mentions the use of BSH and BSSB in clinical studies in Japan See also Joel et al., "Boron Neutron Capture Therapy of Intracerebral Rat Gliosarcomas", Proc. Natl. Acad. Sci. USA, 87, 9808 (1990). See also U.S. Statutory Invention Registration No. H505 to Slatkin et al.
Chemical methods for halogenating, for example iodinating, decaboranes and dodecaboranes are described by Knoth et al., "Chemistry of Boranes IX Halogenation of B.sub.10 H.sub.10.sup.-2 and B.sub.12 H.sub.12.sup.-2 ", Inorg. Chem., 3(2), 159-167 (1964). The article is limited to the particular synthetic methods described, and does not describe or suggest any application of iodinated boranes to BNCT. Unlike the present invention which describes the use of sulfidohydroboranes, Knoth et al., do not describe or suggest sulfur-containing boranes in that particular article, although Knoth is the principal author of the first publication that described the synthesis of BSH, see Knoth et al., "Chemistry of Boranes. XIX. Derivative Chemistry of B.sub.10 H.sub.10.sup.-2 and B.sub.12 H.sub.12.sup.-2 ", J. Am. Chem. Soc., 86, 3973-3983 (1964).
Therefore, it would be advantageous to improve prospects for clinical BNCT that facilitates the selective uptake by tumors of a non-specific halogenated .sup.10 B-carrier and the simultaneous visualization of iodine-labeled .sup.10 B concentrations within a patient for purposes of targeting a therapeutic neutron beam.
Accordingly, it is a purpose of the present invention to provide iodinated, boron-containing compounds that are useful in BNCT and that simultaneously enable visualization of the compound for purposes of rapidly and directly targeting the tumor and estimating the neutron irradiation dose.
It is also a goal of the present invention to provide an improved method of BNCT in which an iodinated boron compound serves as the therapeutic agent and, at the same time, enables the targeting of a neutron beam.
It is a further purpose of the present invention to provide methods for the synthesis of iodinated sulfidohydroborane compounds useful for BNCT and visualization of the boron biodistribution of these compounds in vivo.